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Potential Role of V iral P roperties in the Pathogenesis of AIDS

Potential Role of V iral P roperties in the Pathogenesis of AIDS. Frank Kirchhoff Institute of Molecular Virology Ulm Medical Center, Germany 6/11 .

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Potential Role of V iral P roperties in the Pathogenesis of AIDS

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  1. Potential Role of Viral Properties in the Pathogenesis of AIDS Frank Kirchhoff Institute of MolecularVirology Ulm Medical Center, Germany 6/11

  2. African primatesrepresent a large reservoirforimmunodeficiencyvirusesand chimpanzees, gorillas and mangabeystransmittedthevirus to humans Bieniasz & Ho Cell 2008 SomeSIV-infectedmonkeyspecies (AGMs, SMs) do notdevelopdisease

  3. HIV-1 istheresultofmultiple cross-speciestransmissions anda recombinationeventand(Baileset al., Science 2003; others) Only oneof at least four independent transmissions of SIVcpzfrom chimpanzees and SIVgor from gorillas to humans led to a pandemic

  4. Specificfeatures of HIV-1: Development

  5. Specificfeatures of HIV-1: Development

  6. Specificfeatures of HIV-1: Development

  7. Specificfeatures of HIV-1: Development

  8. Specificfeatures of HIV-1: Development

  9. Specificfeatures of HIV-1: Development

  10. Specificfeatures of HIV-1: Development

  11. Courtesy Paul Spearman Specificfeatures of HIV-1: Vpu • degrades CD4 (Willey et al., 1992; Bouret al., 1995) • antagonizes tetherin(Neil et al., 2008; Van Dammeet al., 2008) • inhibits surface expression of CD1d(Moll et al., 2010) • down-modulates NTB-A (Shah et al., 2010) Vpu:facilitatestherelease of fullyinfectiousvirions and counteractsinnateimmunityfactors Perez-Caballeroet al., Cell 2009 Richard and Cohen, 2010

  12. Specificfeatures of HIV-1: Vpu The evolution of a fully functional Vpu protein may have been a prerequisite for the effective spread of HIV-1 M strains (Sauteret al. 2009) Sauter et al., Human Mutation, in press

  13. Tetherin Tetherin TM Vpu CT Nef Whydid HIV-1 M switchfromNef to Vputo antagonizetetherin? (Jiaet al., 2009; Sauter et al., 2009; Zhang et al. 2009) SIVcpz & SIV gor HIV-1 M & N Humantetherincontains a deletionthatrendersit resistent to Nef

  14. Specificfeatures of HIV-1: Lack of Nef-mediateddown-modulation of TCR-CD3 Kirchhoff, Nat. Rev. Micro. (2009)

  15. Specificfeatures of HIV-1: Lack of Nef-mediateddown-modulation of TCR-CD3 (Schindler et al., Cell 2006; PLOS Path. 2008; Arhelet al., 2009)

  16. Specificfeatures of HIV-1: Lack of Nef-mediateddown-modulation of TCR-CD3 Failure to effectivelydisrupttheimmunologicalsynapsebetweeninfected human T cellsandAPCs(Arhelet al., J. Clin. Invest. 2009) Most primatelentivirusespreventtheinteractionbetweenT cellsandAPCs, whereasHIV-1 just deregulatesit

  17. Specificfeatures of HIV-1: Lack of Nef-mediateddown-modulation of TCR-CD3 Viremic HIV-2 infected Human individuals SIVsmm infected Sooty mangabeys Correlates with low numbers of CD4+ T cells in vivo(Schindler et al., PLOS Path., 2008; Khalid et al., unpublished data)

  18. Role of Vpu & Nef-mediateddown-modulationof TCR-CD3 in viralpathogenesis? Generation and analysis of an „HIV-1-like“ SIVagm Chlorocebussabaeus

  19. Wildtype SIVagm (no Vpu, CD3 down) and the „HIV-1-like“ derivative (Vpu, no CD3 down-modulation) maintain high VLs Thus far no marked differences in CD4+ T cell counts or the clinical outcome but increased T cell proliferation in AGMs infected with SIVs expressing the HIV-1 Nef

  20. Specificfeatures of HIV-1: Links betweenVpu, Nef and Envfunction? Theemergence of CXCR4-tropic SIVsmmstrainsisassociatedwithsevere CD4+ T celldepletionbutnotsufficient to induce AIDS in SMs(Milushet al., 2007; Gordon et al., 2007) This lack of diseaseisassociatedwith double-negative T cells(Milushet al., 2011) Tropismfor CXCR4+ T cells: Loss of CD3 down-modulation tofacilitate T cellactivation

  21. HIV-1 Vpu: CD4, tetherin Nef: no CD3 modulation, weakeffect on CD28 and CXCR4 Frequently CXCR4-tropic Whatwe do know: HIV-1isdifferentfromSIVsmm & SIVagm • SIVsmm, SIVagm • No Vpu • Nef: effectivemodulation of CD3, CD28 and CXCR4tetherinantagonism • Rarely CXCR4-tropic Deregulates T cellactivation Block T cellactivation These propertiesaffect T cellactivationin vitro andmaybelinked Whatwedontknow: Howimportantaretheseviralfeaturesforthesystemiclevels of immune activationand theclinicaloutcome of infection?

  22. Acknowledgments Beatrice H. Hahn Hui Li Frederic Bibollet-Ruche Matthis Kraus (Alabama, USA) Ulrich Schubert Jörg Votteler (Erlangen, Germany) Paul Bieniasz Theodora Hatziioannou (New York, USA) Guido Silvestri (Philadelphia, USA) Cristian Apetrei Ivona Pandrea (Tulane, USA) Paul Sharp Elisabeth Bailes (Nottingham, UK) Donald Sodora (Seattle, USA) Michaela Müller-Trutwin (Paris, France) Christiane Stahl-Hennig Ulrike Sauermann (DPZ, Germany) Martine Peeters (Montpellier, France)

  23. Thanksforyourattention Institute of MolecularVirology, Ulm Funding: DFG, NIH

  24. Virus-host interactions and the virological and clinical outcome of primate lentiviralinfections

  25. Specificfeatures of HIV-1: Lack of Nef-mediateddown-modulation of TCR-CD3 Increased T cellactivation and AICD in virallyinfected T cells(Schindler et al., 2006)

  26. Specificfeatures of HIV-1: Lack of Nef-mediateddown-modulation of TCR-CD3 Increasedexpression of deathreceptorsand activationmarkersin PBMC cultures

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